Red blood cells reversibly bind oxygen under physiological conditions and mediate the continuous delivery of oxygen to the tissues that is needed for cellular respiration. Blood transfusion constitutes a traditional treatment option for patients exhibiting red blood cell deficiency. Blood substitutes (i.e., artificial oxygen carriers) have been proposed as a cell-free means of avoiding the transmission of infectious agents (e.g., human immunodeficiency virus or hepatitis virus) that can accompany blood transfusion. In addition, blood substitutes can also be advantageous over allogeneic red blood cell transfusion in that the lack of iso-agglutinating antigens in blood substitutes obviates the need for blood typing and screening and avoids potentially adverse reactions that can result from a mismatch of the donor blood and the transfusion recipient. The lack of cross-matching requirements allows virtually immediate availability for transfusion of a blood substitute in the critical early periods of trauma or hemorrhage. Blood substitutes can also undergo storage for prolonged periods and retain their activity. See, e.g., Spahn et al. (2005) Curr Pharm Des. 11(31):4099 and Greenburg et al. (2004) Crit. Care 8 Suppl 2:S61.
A heme-based oxygen carrier is a cell-free blood substitute that contains heme combined with a native or modified protein (e.g., globin or albumin) or other molecule and that is capable of delivering oxygen to tissues. Heme-based oxygen carriers (e.g., hemoglobin-based oxygen carriers) can be used, for example, to prevent or treat hypoxia resulting from anemia, blood loss (e.g., from acute hemorrhage or during surgical operations), or shock (e.g., volume deficiency shock, anaphylactic shock, septic shock, or allergic shock). Heme-based oxygen carriers can be infused for essentially any purpose for which banked blood is administered to patients. See, e.g., Artificial Oxygen Carrier: Its Front Line (Koichi Kobayashi et al. eds., 2005). In addition, heme-based oxygen carriers can be administered to a subject to improve myocardial function and reduce myocardial infarct size after acute coronary ischemia and reperfusion. George et al. (2006) Am. J. Physiol. Heart Circ. Physiol. 291(3):H1126-37 and Caswell et al. (2005) Am. J. Physiol. Heart Circ. Physiol. 288:H1796-1801. Despite the foregoing advantages, administration of heme-based oxygen carriers often triggers vasoconstriction in recipients. This may account for the excess mortality due to heart attacks and strokes in clinical trials using hemoglobin-based oxygen carriers. Vasoconstriction due to heme-based oxygen carriers can cause coronary vasospasm, cerebral vasospasm, pulmonary vasospasm, renal vasospasm, and spasm of any or all other blood vessels and smooth muscles in the body, including those of the gastrointestinal tract.